8.6.1 Aromatic Nitrogen Compounds
Investigations of the binding of N-aryl carcinogens to nucleic acids began in the 1890s with an investiga-
tion of the epidemiology of bladder cancer among workers in a Basel dye factory. The list of chemicals
now banned is extensive, but by no means definitive: some examples of proscribed aromatic amines, nitro
compounds and azo dyes are illustrated (Figure 8.13).^33
Aromatic aminesof this sort are substrates for oxidation by cytochrome P-450 isozymes, which give
either phenols, that are inactive and safely excreted, or hydroxylamines. Conjugation of the latter by sul-
fotransferase oracetate transferaseenzymes converts these proximate carcinogens into ultimate carcino-
gensthat can bind covalently to nucleic acid bases, especially to guanine.
The competition between such alternative ‘safe’and ‘hazardous’metabolic processes is illustrated for
2-acetylaminofluorene(Figure 8.14a). The corresponding guanine nucleoside adducts have been isolated
304 Chapter 8
PtFigure 8.12 (a) Structures of cisplatin and some more recent analogues under clinical development. (b) A 2.4Å
molecular structure of oxaliplatin intrastrand cross-link formed with a duplex dodecamer d(CCTCTG-
GTCTCC).d(GGAGACCACAGG) showing the GG step. Similar intrastrand d(GpG) cross-link
structures occur for {cis-Pt(NH 3 ) 2 }^2 and {cis-Pt(NH 3 )(CyNH 2 )}^2 with the same dodecamer. The
minor groove is widened and shallow, presenting an excellent target for DNA-binding proteins
(Adapted from Ref. 31. © (2001), with permission from the American Chemical Society)